Detecting Liquid Remnants of Solid Tumors: Circulating Tumor DNA Minimal Residual Disease
Open accessAbstract
Growing evidence demonstrates that circulating tumor DNA (ctDNA) minimal residual disease (MRD) following treatment for solid tumors predicts relapse. These results suggest that ctDNA MRD could identify candidates for adjuvant therapy and measure response to such treatment. Importantly, factors such as assay type, amount of ctDNA release, and technical and biological background can affect ctDNA MRD results. Furthermore, the clinical utility of ctDNA MRD for treatment personalization remains to be fully established. Here, we review the evidence supporting the value of ctDNA MRD in solid cancers and highlight key considerations in the application of this potentially transformative biomarker.Significance: ctDNA analysis enables detection of MRD and predicts relapse after definitive treatment for solid cancers, thereby promising to revolutionize personalization of adjuvant and consolidation therapies.
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A growing body of evidence shows many clinical uses for ctDNA in adults with solid tumors, from prognostication and minimal residual disease evaluation to detection of targetable alterations.
“There is a growing body of data demonstrating numerous clinical applications for ctDNA in adults with solid tumors, ranging from prognostication and evaluation of minimal residual disease (MRD) to detection of targetable alterations.7–12”
From Clinical Liquid Biopsy Testing for Detection of Actionable Genomic Alterations in Children and Young Adults With Advanced Solid Tumors on the GAIN Study (2026) · cites this paper as [7]
The clinical utility of ctDNA for directing treatment escalation or de-escalation in early-stage solid tumors remains under prospective evaluation.
“although its clinical utility for directing treatment escalation or de-escalation remains under prospective evaluation [ 9 , 10 ].”
From Signals Alongside Scans: A Genomics-Guided Framework for Liquid Biopsy in Bone and Soft-Tissue Sarcomas (2026) · cites this paper as [9]
Across early-stage solid tumors, postoperative or post-treatment ctDNA detection is consistently associated with a higher risk of recurrence.
“Across early-stage solid tumors, postoperative or post-treatment ctDNA detection is consistently associated with a higher risk of recurrence”
From Signals Alongside Scans: A Genomics-Guided Framework for Liquid Biopsy in Bone and Soft-Tissue Sarcomas (2026) · cites this paper as [9]
ctDNA analysis has developed most rapidly in common epithelial malignancies, where it is used for selected advanced-cancer genotyping and is being evaluated for MRD and molecular relapse monitoring after curative-intent therapy.
“ctDNA analysis has developed most rapidly in common epithelial malignancies, where it is now used for selected advanced-cancer genotyping scenarios and is being actively evaluated for MRD and molecular relapse monitoring after curative-intent therapy [ 5 , 9 , 10 ].”
From Signals Alongside Scans: A Genomics-Guided Framework for Liquid Biopsy in Bone and Soft-Tissue Sarcomas (2026) · cites this paper as [9]
In early-stage solid tumors, ctDNA detection after curative-intent therapy has shown strong clinical validity for predicting future relapse.
“In early-stage solid tumors, ctDNA detection after curative-intent therapy has shown strong clinical validity for predicting future relapse”
From Signals Alongside Scans: A Genomics-Guided Framework for Liquid Biopsy in Bone and Soft-Tissue Sarcomas (2026) · cites this paper as [9]
Among liquid-biopsy analytes, ctDNA is currently the most clinically mature for sarcoma monitoring because it can capture tumor-specific genomic and epigenomic alterations through a minimally invasive and repeatable blood test.
“Among liquid-biopsy analytes, ctDNA is currently the most clinically mature for sarcoma monitoring because it can capture tumor-specific genomic and epigenomic alterations through a minimally invasive and repeatable blood test [ 5 , 9 ].”
From Signals Alongside Scans: A Genomics-Guided Framework for Liquid Biopsy in Bone and Soft-Tissue Sarcomas (2026) · cites this paper as [9]
MRD detection requires greater analytical sensitivity than baseline genotyping or advanced-disease resistance monitoring because tumor-derived DNA may represent only a very small fraction of total cell-free DNA after definitive therapy.
“MRD detection requires greater analytical sensitivity than baseline genotyping or advanced-disease resistance monitoring, because tumor-derived DNA may represent only a very small fraction of total cell-free DNA after definitive therapy [ 5 , 9 ].”
From Signals Alongside Scans: A Genomics-Guided Framework for Liquid Biopsy in Bone and Soft-Tissue Sarcomas (2026) · cites this paper as [9]
Tumor-informed assays can improve sensitivity by tracking patient-specific alterations identified from tissue sequencing.
“Tumor-informed assays can improve sensitivity by tracking patient-specific alterations identified from tissue sequencing”
From Signals Alongside Scans: A Genomics-Guided Framework for Liquid Biopsy in Bone and Soft-Tissue Sarcomas (2026) · cites this paper as [9]
Tumor-naïve approaches may be useful when tissue is unavailable or when methylation, fragmentomic, or copy-number signals provide sufficient discriminatory power.
“whereas tumor-naïve approaches may be useful when tissue is unavailable or when methylation, fragmentomic, or copy-number signals provide sufficient discriminatory power [ 9 , 10 , 11 , 12 ].”
From Signals Alongside Scans: A Genomics-Guided Framework for Liquid Biopsy in Bone and Soft-Tissue Sarcomas (2026) · cites this paper as [9]
MRD detection requires substantially greater analytical sensitivity than baseline genotyping because tumor-derived DNA may be present at very low levels after surgery or definitive therapy.
“MRD detection is the most clinically ambitious use of ctDNA in sarcoma. It requires substantially greater analytical sensitivity than baseline genotyping because tumor-derived DNA may be present at very low levels after surgery or definitive therapy [ 5 , 9 , 10 , 11 , 12 ].”
From Signals Alongside Scans: A Genomics-Guided Framework for Liquid Biopsy in Bone and Soft-Tissue Sarcomas (2026) · cites this paper as [9]
Tumor-informed assays can track multiple patient-specific alterations at high depth, improving sensitivity for low-level residual disease.
“Tumor-informed assays can track multiple patient-specific alterations at high depth, improving sensitivity for low-level residual disease [ 9 , 16 ].”
From Signals Alongside Scans: A Genomics-Guided Framework for Liquid Biopsy in Bone and Soft-Tissue Sarcomas (2026) · cites this paper as [9]
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- Authors
- Moding, E. J., Nabet, B. Y., Alizadeh, A. A., & Diehn, M.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Alizadeh, Ash A.
- Diehn, Maximilian
- Venue
- Cancer Discovery
- Published
- 2021-12-01
- Volume
- 11
- Issue
- 12
- Pages
- 2968-2986
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC8976700
- OpenAlex
- W3214322235
- Cited by
- 325
- References
- 114
- Citations by year
- 2026: 66 · 2025: 75 · 2024: 74 · 2023: 81 · 2022: 28 · 2021: 1
- FWCI
- 5.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (5R25CA180993)
- Postdoctoral Research Fellowship (134031-PF-19-164-01-TBG)
- Leukemia and Lymphoma Society NCI (R01CA257655, R01CA233975, R01CA188298)
- NCI (R01CA188298, R01CA233975, R01CA244526, R01CA254179)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Keywords
- circulating tumor DNA, minimal residual disease, solid tumors, recurrence prediction, liquid biopsy, adjuvant therapy, treatment response monitoring, liquid biopsy biomarkers, personalized treatment
- MeSH terms
- Circulating Tumor DNA, Humans, Neoplasm Recurrence, Local, Biomarkers, Tumor, Neoplasm, Residual
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